Biomedical subjects
Publications and source records attributed to S Goldstein.
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Poor growth in diabetes involves low circulating levels of somatomedins/insulin-like growth factors (IGFs), largely reflecting decreased growth factor release by the liver. To define regulatory mechanisms, circulating IGF-1 was compared with levels of a high mol wt putative hepatic IGF-1 precursor and hepatic IGF-1 mRNA in a model of progressive severity of diabetes in rats. Streptozotocin administered at 36, 72, 144, and 288 mg/kg produced graded metabolic decompensation 2 days later, from minimal hyperglycemia with continued weight gain at 36 mg/kg, to marked hyperglycemia, ketonemia, and weight loss at 288 mg/kg (all P less than 0.001). Total serum IGF-1 measured by RIA was unchanged with the 36 and 72 mg/kg doses of streptozotocin (471 +/- 19 and 439 +/- 27 ng/ml, respectively, vs. 517 +/- 27 ng/ml in controls) despite serum glucose greater than 400 mg/dl. With streptozotocin 144 and 288 mg/kg, serum IGF-1 fell to 131 +/- 27 and 142 +/- 10 ng/ml, respectively (both P less than 0.005 vs. controls). Serum IGF-1 was correlated strongly with serum beta-hydroxybutyrate and body weight (r = -0.88 and 0.91, respectively, P less than 0.0001), and less strongly with serum glucose (r = -0.59, P less than 0.0002). Extractable hepatic content of a high mol wt form of immunoreactive IGF-1 (a putative precursor) was unchanged at the two lowest doses of streptozotocin (68 +/- 4 and 83 +/- 9 ngeq/g vs. 67 +/- 4 in controls), but decreased to 16 +/- 3 and 29 +/- 4 ng/g at the two highest doses (both P less than 0.001 vs. controls).(ABSTRACT TRUNCATED AT 250 WORDS)
Ambulatory electrocardiograms obtained in 69 patients enrolled in the nocturnal oxygen therapy trial group were examined for frequency and significance of arrhythmias in patients with stable chronic obstructive lung disease. Ventricular premature beats occurred in 83 percent, ventricular bigeminy in 68 percent, paired ventricular premature beats in 61 percent, and nonsustained ventricular tachycardia in 22 percent of the patients. Supraventricular tachycardia occurred in 69 percent. Repetitive ventricular arrhythmia occurred in 64 percent of the patients, and was significantly more frequent in men and in patients with edema or elevated PCO2. Ventricular premature beats greater or equal to 25 per hour occurred in 35 percent of the patients. Univariate and multivariate Cox proportional hazards analysis showed that a history of coronary heart disease, increased sinus heart rate and decreased maximum work load (measured by maximal treadmill exercise test)--but not arrhythmias--were predictors of death.
It is shown that the copper zinc superoxide dismutase is unique in its ability to catalyze O2- dismutation in vivo in contrast to other copper compounds which have this feature only in vitro. The reasons for this difference are discussed in terms of kinetic and thermodynamic parameters.
Usually the toxicity of superoxide is attributed to its ability to reduce metal ions and subsequently reoxidation of the metal by hydrogen peroxide yields deleterious oxidizing species. As many other nontoxic biological reductants reduce metal compounds, we suggest that part of the mechanism of superoxide toxicity results from its ability to oxidize metal ions bound to biological targets, which subsequently degrade the target via an intramolecular electron transfer reaction.
Of 270 patients successfully resuscitated from out-of-hospital cardiac arrest, 16% had no evidence of coronary heart disease. In these 43 patients, other forms of heart disease were found in 81% (35/43): cardiomyopathy in 18 patients, valvular disease in six, congenital heart disease in two, and primary arrhythmia in nine. Seven patients had evidence of only pulmonary disease and one had pancreatitis as his precipitating event. Nineteen of the 43 patients (44%) had serum potassium less than 3.6 mEq l-1 in the initial blood sample after cardiac arrest. One- and two-year mortalities were 30% and 43%, respectively, for the group, which is similar to one-year (20%) and two-year (35%) mortalities of the 227 resuscitated patients with coronary heart disease. Patients who survive a sudden death experience and who have no evidence of coronary artery disease are a unique but heterogeneous group who usually have identifiable cardiac or pulmonary disease.
The effect of the beta-adrenergic blocking agent propranolol on morbidity and mortality risk after acute myocardial infarction was studied relative to coronary anatomy and left ventricular (LV) ejection fraction in a subset of 406 patients participating in a randomized study of 3,837 patients in the Beta Blocker Heart Attack Trial (BHAT). Median follow-up for this subset of patients was 28 months. The mortality rate was 2% (2 of 100) in patients with 2- and 3-vessel coronary artery disease taking propranolol and 10% (12 of 126) in those taking placebo (p less than 0.02). In patients with 2- and 3-vessel coronary artery disease with decreased LV function (defined as ejection fraction less than 50%), no patient taking propranolol died, whereas 17% (7 of 42) taking placebo died (p less than 0.04). The salutary effect of propranolol on mortality in the larger BHAT after acute myocardial infarction also was evident in this population studied in regard to their coronary and LV anatomy and function.
We describe an ELISA technique able to recognize malondialdehyde-modified low-density lipoproteins (LDL). For this purpose we produced antibodies to malondialdehyde-LDL, specific for the malondialdehyde modification of LDL; these antibodies recognized essentially malondialdehyde-LDL. Coating ELISA plates with the antibodies to malondialdehyde-LDL and using peroxidase-labelled antibodies to LDL, which reveal only apolipoprotein B, we obtained an accurate method of detecting malondialdehyde-modified apolipoprotein B. Preliminary studies demonstrated that this method allows the detection of lipoproteins containing malondialdehyde-modified apolipoprotein B in the serum of patients with cardiovascular diseases.
Aspirin interacts in vitro with human low-density lipoprotein (LDL), which results in a decrease in free amino groups of apolipoprotein B and an increase of electrophoretic mobility of the particle. The aspirin-treated LDL was less efficiently recognized than native LDL by the apo B/E receptor of fibroblasts. These results suggest that aspirin in long-term treatment could influence the LDL-receptor pathway. However, aspirin-treated LDL did not bind to the scavenger receptor of macrophages.
CI-930, a new type III phosphodiesterase inhibitor, was evaluated for treatment of refractory congestive heart failure. The hemodynamic, pharmacokinetic and clinical response to the drug was determined in 10 patients. At the peak plasma concentration after intravenous CI-930, cardiac index increased from 2.0 to 2.7 liters/min/m2 (p less than 0.002), pulmonary artery wedge pressure decreased from 26 to 17 mm Hg (p less than 0.001) and systemic vascular resistance decreased from 1,999 to 1,471 dynes cm-5 (p less than 0.05). Heart rate and blood pressure did not change significantly. Similar changes were observed with oral CI-930. Peak CI-930 plasma concentration occurred 1.2 +/- 0.8 hours after oral administration. Beneficial hemodynamic effects were sustained 12 to 18 hours after the oral dose. The sustained hemodynamic effects observed after oral administration appear to be related to an active metabolite of CI-930 that has prolonged duration of action and slow washout. The drug was well tolerated and has potential for treatment of congestive heart failure.
We have previously described the oxidative inactivation of several key metabolic enzymes by a variety of mixed function oxidation systems. Because many of the enzymes which are inactivated have been shown by others to accumulate as inactive or less active forms during cellular aging, we have examined the levels of oxidatively modified proteins in two model systems used for studies on aging. The results show that levels of oxidatively modified proteins increase with age in circulating erythrocytes, and this change is correlated with the loss of marker enzyme activity. Our studies also show that in cultured fibroblasts from normal donors the levels of oxidatively modified proteins increase only after the age of 60. However, the levels of oxidatively modified proteins in fibroblasts from individuals with progeria or Werner's syndrome are significantly higher than age-matched controls. Moreover, treatment of glucose-6-phosphate dehydrogenase with a mixed function oxidation system leads to oxidative modification and increased heat lability of the enzyme. Taken together these results suggest that loss of functional enzyme activity and increased heat lability of enzymes during aging may be due in part to oxidative modification by mixed function oxidation systems.
Afternoon continuous plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were first shown to be a good representation of the mean 24-hour plasma level of MHPG in 18 normal subjects. Then, after the stability of the procedure was tested and retested, the afternoon continuous test for plasma MHPG levels was performed in 57 normal subjects and 42 endogenously depressed patients. A significant correlation between plasma MHPG levels and age was found in normal subjects and depressive patients. When the variable of age was taken into account, a distinct pattern of increasing plasma MHPG levels with age--the "MHPG per age"--was found in the depressed patients, especially the women, who could be divided into high or low MHPG per age groups. There was almost no association between plasma levels of MHPG or MHPG per age values and clinical symptoms, and the two biologic subgroups did not differ clinically.
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Acute and chronic hemodynamic effects at rest and during exercise of a new dihydropyridine calcium antagonist, nicardipine hydrochloride, were studied in 10 patients with chronic heart failure. Acute intravenous administration of nicardipine resulted in a significant decrease in arterial blood pressure, systemic vascular resistance, and pulmonary capillary wedge pressure. There was a significant increase in cardiac index, stroke volume index, and the left ventricular stroke work index. Cardiac index measured at peak exercise increased significantly when compared with the cardiac index obtained at peak exercise before the infusion. After 9 days of continuous therapy with nicardipine, 30 mg three times a day, a significant decrease in arterial blood pressure and systemic vascular resistance and a significant increase in the cardiac index, stroke volume index, and left ventricular stroke work index at rest were observed in response to a single oral dose of 30 mg nicardipine. Data at peak exercise were also obtained before and 2 hours after the oral administration of nicardipine. With this comparison there was a significant increase in cardiac index, stroke work index, and exercise duration. It is concluded that in this group of patients with severe chronic heart failure, nicardipine enhanced myocardial performance during rest and exercise and this enhancement is sustained after 9 days of oral therapy.
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The J.774 murine macrophage cells were cultured in suspension in Teflon flasks. When allowed to attach on culture plastic dishes, a 2-3-fold increase in transferrin binding was observed. This occurred in 10 min, reached a steady state at 60 min, remained stable for several hours and was reversible after resuspension of the cells at 37 degrees C. The phenomenon was not dependent on the synthesis of new protein. An opposite change of acetyl LDL receptors was observed, with a threefold decrease of the binding 1 h after the attachment of the cells. The increase of transferrin binding affected almost equally the cell surface and the intracellular sites; therefore it could not be related to a simple shift between these two compartments. It is suggested that the attachment of the cells induced a recruitment of binding sites from a 'silent' pool of receptors. Serum factors, as well as phorbol esters and db-cAMP potentiated the effect of anchorage.
In the Beta Blocker Heart Attack Trial, a double blind, randomized, controlled study, patients taking propranolol (180 or 240 mg/day) initiated 5-21 days post myocardial infarction had 26% fewer deaths than those taking placebo over a 25 month (mean) followup. Detailed analysis of the circumstances surrounding the BHAT deaths failed to reveal any striking difference between propranolol and placebo in the type of clinical event preceding death, the incidence and type of acute and prodromal signs and symptoms, the location of death, the activity preceding death or the percentage of deaths that were sudden or instantaneous, suggesting that propranolol may exert an "across the board" effect and improve survival by a combination of mechanisms. An unexpected finding was that the protective effect of propranolol appeared to occur during the hours of 10 p.m. to 7 a.m.
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